IE55285B1

IE55285B1 - Polyene compounds

Info

Publication number: IE55285B1
Application number: IE1471/83A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1982-06-24
Filing date: 1983-06-23
Publication date: 1990-08-01
Also published as: DK159392C; BE897118A; DK287083A; GB2156351A; SE8303539L; FR2529201A1; DE3321662C2; GB8317129D0; IT8321721A0; DE3321662A1; DK287083D0; ATA230583A; GB2156351B; IT1212753B; AT392780B; CA1276032C; NZ204628A; CH651007A5; IL69028A0; SE8303539D0

Abstract

This invention provides ethyl (all-E)-5-formyl-4-methyl-2,4-pentadienoate which is useful as an intermediate for the manufacture of pharmaceutically valuable polyene compounds which form the subject of copending Application No. 8317129. [GB2156351A]

Description

2 65285 The present invention is concerned with novel polyene compounds, a process for their manufacture and pharmaceutical preparations which contain these polyene compounds The polyene compounds provided by the present in-5 vention are compounds of the general formula CH—COR2 CH, CH, 1 I 3 | 3 R — C=CH—CH=C—CH wherein R is a group of the formula or R3 2 R is hydroxy, Cn-C^-alkoxy, amino, mono- 1 6 -{Cj^-Cg-alkyl) amino or di- (Cj-Cg-alkyl) - 3 4 amino, R is c^-Cg-alkyl or halogen, R 6 is C^-Cg-alkyl, R is Gj-Cg-alkoxy, R is hydrogen or C^-Cg-alkyl and R7 is Cj-Cg-alkyl or halogen, and pharmaceutically acceptable salts of the carboxylic acids of formula I.

Preferred groups of'formula (c) are those in which R3, R4 and R7 are Cj-Cg-alkyl, R5 is C1-Cg-alkoxy and R6 is hydrogen.

Alkyl groups and the alkyl moieties present in and alkylamino groups can be straight-chain or branched-chain such as, for example, the methyl, ethyl, isopropyl or 2-methylpropyl group, with methyl being especially preferred .

Methylamino and ethylamino are examples of alkylamino groups and diethylamino is an example of a dialkylamino group.

The compounds of formula I and the pharmaceutically acceptable salts of the carboxylic acids of formula I 4 can be manufactured in accordance with the invention by reacting a compound of the general formula R^A with a compound of the general formula CH, IX I 3 2 B — CH— C — CH—CH— COR 1 2 10 , wherein R and R have the significance given above and either A represents a 1-(triphenylphosphonium)-ethyl group of the formula H3C-CH-P[X]3+Y~, in which X represents phenyl and Y~ represents the anion of an organic or inorganic acid, and B represents formyl; or A represents acetyl and B represents a dialkoxyphosphinylmethyl group of the formula -CH^-P[Z]in which Z represents a C^-Cg-0 15 -alkoxy group; and, if desired, converting a carboxylic acid ester obtained into a carboxylic acid or a carboxylic acid amide and, also if desired, converting a carboxylic acid obtained into a pharmaceutically acceptable salt.

The chloride, bromide or hydrosulphate ion is the preferred inorganic acid anion denoted by Y and the tosyl-oxy ion is the preferred organic acid anion denoted by Y.

The reaction of a formyl compound of formula II with a phosphorane is carried out in a manner known per se in 20 5 the presence of an acid-binding agent, for example in the presence of a strong base such as, for example, butyl lithium, sodium hydride or the sodium salt of dimethyl sulphoxide, if desired in a solvent, for example in an 5 ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, at a temperature between room temperature and the boiling point of the reaction mixture.

The reaction of a phosphonate of formula II with a 10 compound of the formula R^COCH^ is also carried out in a manner known per se in the presence of a base and, preferably, in the presence of an inert organic solvent, for example in the presence of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or 15 1,2-dimethoxyethane or in the presence of a sodium alcoho-late in an alkanol (e.g. sodium methylate in methanol), at a temperature between 0°C and the boiling point of the reaction mixture.

The reactions described earlier can also be carried 20 out in situ, i.e. without isolating the phosphonium salt or phosphonate in question.

A carboxylic acid ester of formula I can be hydrolyzed in a manner known per se, for example by treatment with 6 alkalis, especially by treatment with aqueous-alcoholic sodium or potassium hydroxide solution at a temperature between room temperature and the boiling point of the reaction mixture, and the resulting carboxylic acid can be 5 amidated either via an acid halide or, as described hereinafter, directly.

A carboxylic acid of formula X can be converted in a manner known per se, for example by treatment with thio-nile chloride, preferably in pyridine, or with phosphorus 10 trichloride in toluene, into the acid chloride which can be converted into an ester by reaction with an alcohol or into a corresponding amide by reaction with an amine.

A carboxylic acid ester can be converted directly into the corresponding amide, for example by treatment with 15 lithium amide. The lithium amide is advantageously reacted at room temperature with the ester in question.

A carboxylic acid of formula X forms pharmaceutically acceptable salts with bases, especially with alkali metal hydroxides and preferably with sodium hydroxide or potassium 20 hydroxide.

Formula I hereinbefore is intended to embrace cis and trans forms. 7 The compounds of formula X can occur as cis/trans mixtures which, if desired and in a manner known per se, can be separated into the cis and trans components or isomerized to the all-trans compounds. The all-trans 5 (all-E) compounds are preferred.

The compounds of formula I and pharmaceutically acceptable salts of the carboxylic acids of formula I are useful as medicaments. They can be used for the topical and systemic therapy of benign and malignant neoplasms 10 and of premalignant lesions as well as for the systemic and topical prophylaxis of these conditions.

They are also suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses accompanied with an intensified or pathologically altered 15 cornification as well as of inflammatory and allergic dermatological conditions. Further, the compounds of formula I and physiologically acceptable salts of the carboxylic acids of formula I can also be used for the control of disorders of the mucous membranes associated 20 with inflammatory or degenerative or metaplastic changes and for the oral treatment of rheumatic diseases, especially those of an inflammatory and degenerative kind which affect the joints, muscles, tendons and other parts of the loco- motor system. Examples of such diseases are primary cronic polyarthritis, spondylarthritis ankylopoetica Bechterew and psoriatic arthritis.

The tumour-inhibiting activity of the compounds of formula I and pharmaceutically acceptable salts of the carboxylic acids of formula I is significant. In the papilloma test £~Europ. J. Cancer 10, 731-737 [1974]_7 a regression of tumours induced with dimethylbenzanthracene and croton oil has been observed. The diameters of the papillomae decrease in the course of 2 weeks by about 49% following the intraperitoneal administration of 50 mg of ethyl (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthyl)-2,4,6-octatrienoate.

The compounds of formula I and pharmaceutically acceptable salts of the carboxylic acids of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations for systemic administration can be manufactured, for exairple, by adding a compound of formula I or a pharmaceutically acceptable salt of a carboxylic acid of formula I as the active ingredient to non-toxic, inert, solid or liquid carriers which are customary per se in such preparations. The pharmaceutical preparations can be administered enterally or parenterally. For enteral administration 9 there are suitable, for example, pharmaceutical preparations in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. For parenteral administration there are suitable pharmaceutical pre-5 parations in the form of infusion or injection solutions.

The dosages in which the compounds of formula I and the pharmaceutically acceptable salts of the carboxylic acids of formula I are administered can vary according to the type of use, the mode of use and the requirements 10 of the patients.

The compounds of formula I and the pharmaceutically acceptable salts of the carboxylic acids of formula I can be administered in amounts of about 0.01 to about 5 mg daily in one or more dosages. A preferred administration form comprises capsules containing about 0.1 mg to about 1.0 mg of active substance.

The pharmaceutical preparations can contain inert as well as pharmacodynamically active additives. Tablets or granulates, for example, can contain a series of binding 20 agents, filling materials, carrier substances or diluents.

Liquid preparations can take the form, for example, of a sterile solution which is miscible with water. Capsules can contain, in addition to the active substance, a filling material or thickening agent. Furthermore, flavour--improving additives, substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present.

The previously mentioned carrier substances and diluents can be organic or inorganic substances? for example, water, gelatine, lactose, starch, magnesium stearate, talc, gum arable and polyalkylene glycols. A prerequisite is that all adjuvants used in the manufacture of the pharmaceutical preparations are non-toxic.

\ For topical administration the compounds of formula X and pharmaceutically acceptable salts of the carboxylic acids of formula I are conveniently used in the form of, e.g. salves, tinctures, creams, solutions, lotions, sprays and suspension. Salves, creams and solutions are preferred. These pharmaceutical preparations for topical administration can be manufactured by mixing a compound of formula I or a pharmaceutically acceptable salt of a carboxylic acid of formula I as the active ingredient with non-toxic, inert, solid or liquid carriers which are customary per se in such preparations and which are suitable for topical treatment. 11 For topical administration there are conveniently used about 0.01% to about 0.3%, preferably 0.2% to 0.1%, solutions and about 0.05% to about 5%, preferably about 0.05% to about 1%, salves or creams.

If desired, an antioxidant (e.g. tocopherol, N- -methyl-y-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene) can be incorporated in the pharmaceutical preparations. 12 The following Examples illustrate the present invention: Example 1 23.4 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetra-5 methy1-2-naphthyl)ethyl]-triphenylphosphonium bromide in 150 ml of dry tetrahydrofuran were treated slowly at -15°C while stirring with 26.25 ml of 1.6 molar butyl lithium (in hexane). After 30 minutes, there were added dropwise at the same temperature 6.72 g (40 mmol) of ethyl 10 (all-E)-5-formyl-4-methyl-2,4-pentadienoate in 30 ml of tetrahydrofuran and the mixture was subsequently stirred at room temperature for a further 2 hours. After the addition of ethyl acetate, the organic phase was shaken with 0.1N hydrochloric acid, washed neutral with water, 15 dried over magnesium sulphate and concentrated on a rotary evaporator. Two-fold crystallization of the residue from about 100 ml of ethanol gave 3.47 g (24%) of ethyl (all-E)--4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)-2,4,6-octatrienoate of melting point 87.5-89°C. 20 A further 1,6 g of pure product could be obtained from the mother liquors by chromatography.

The ethyl (all-E)-5-formyl-4-methy1-2,4-pentadienoate which forms the subject of O.K. Divisional Application No. 8510717, can be prepared as follows: 13 (a) 43.23 g of triethyl phosphonoacetate are added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. 25.0 g (0.18 mol) of γ-acetoxy-tiglic aldehyde in 50 ml of tetrahydrofuran are subsequently added dropwise at 0-5°C.

The mixture is stirred at room temperature for 20 hours, diluted with 200 ml of ethyl acetate, washed with saturated sodium chloride solution and dried over magnesium sulphate. Concentration and distillation at 103°C/0.35 mmHg give 28.6 g (76%) of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate. (b) 27.5 g of ethyl 6-acetoxy-4~methy1-2,4-hexadienoate, 20 g of sodium carbonate and 2 ml of triethanolamine are heated to reflux for 3 hours in 250 ml of ethanol. After the addition of ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over mag-15 nesium sulphate and concentrated. Distillation at 110°C/ 0.4 mmHg give 15.7 g (71%) of ethyl 6-hydroxy-4-methyl--2,4-hexadienoate. (c) 11.7 g of ethyl 6-hydroxy-4-methyl-2,4-hexadienoate in 200 ml of dichloromethane are stirred at room temperature 20 for 4 hours with 30 g of manganese (IV) oxide. The solution is filtered and concentrated and the residue is then recrystallized from hexane/cyclohexane. There are obtained 9.1 g (78%) of ethyl 5-formyl-4-methyl-2,4-pentadienoate of melting point 48-49°C. 14 Example 2 In a manner analogous to that described in Example 1, from 1-methyl-3-(2,6,6-trimethyl-l-cyclohexen-l-yl)allyl--triphenylphosphonium chloride and ethyl 5-fonnyl-4-methyl-5 -2,4-pentadienoate there is obtained ethyl 4,7-dimethyl-9--(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8-nonatetra-enoate of melting point 65-66°C (from methanol).

Example 3 In a manner analogous to that described in Example 1, 10 from l-methyl-3-(2,3,6-trimethyl-4-methoxyphenyl)allyl- -triphenylphosphonium chloride and ethyl 5-£ormyl-4-methyl--2,4-pentadienoate there is obtained ethyl (all-E)-9-- (4-methoxy-2,3,6-trimethylphenyl)-4,7-dimethyl-2,4,6,8--nonatetraenoate.

Example 4 9 g of ethyl (all-E)-4-methyl-7-(5,6,7,8-tetrahydro--5,5,8,8-tetramethy1-2-naphthyl)-2,4,6-octatrienoate are dissolved in 200 ml of ethanol and the solution is treated with a solution of 8.2 g of potassium hydroxide in 20 ml 20 of water. After stirring at room temperature for 18 hours, the mixture is poured into ice-water, acidified with 2N sulphuric acid and the precipitated acid is filtered off. After recrystallization from methanol, there are obtained 7.8 g of (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthyl)-2,4,6-octatrienoic acid in the 5 form of yellow crystals of melting point 232-234°C.

Example 5 4.5 g of (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-2-naphthyl)-2,4,6-octatrienoic acid are dissolved in 200 ml of tetrahydrofuran and the solution 10 is treated with 2.6 g of l,l'-carbonyldiimidazole. After stirring at room temperature for 3 hours, the mixture is cooled to 5-10°C and a stream of ethylamine is introduced during 1 hour. After removing the cooling bath, the mixture is stirred at room temperature overnight. The 15 mixture is subsequently poured into ice-water, acidified with 6N sulphuric acid and extracted with ethyl acetate.

The organic phase is washed with 2N sodium carbonate solution and with saturated sodium chloride solution, dried over sodium sulphate and evaporated. After a further 20 purification of the crude product by chromatography on silica gel using methylene chloride/acetone (95:5) for the elution and recrystallization from toluene, there are obtained 1.6 g of N-ethyl 4-methyl-7~(5,6,7,8-tetrahydro--5,5,8,8-tetramethyl-2-naphthyl)-2,4,6-octatrienamide in 16 the form of yellow crystals of melting point 150-159°C.

Example A Capsules can contain the following ingredientsj Ethyl (all-E)-4-methyl-7-(5/6,7,8-tetra 5 hydro-5,5,8,8-tetramethy1-2-naphthyl)- 0.1 mg 50.5 mg 98.9 mg 0.5 mg -2,4,6-octatrienoate Wax mixture Vegetable oil Ethylenediaminetetraacetic acid tri-10 sodium salt

Claims

17 1. I 3 I 3 2 R — C = CH—CH= C — CH—CH—COR wherein is a group of the formula or

1. A compound of the general formula

2. A compound according to claim 1, wherein R1 is a 3 4 7 group of formula (c) and R , R and R are C.-c,-alkyl, X o R1 is C^-Cg^alkoxy and R^ is hydrogen. 2 R is hydroxy, C-^-Cg-alkoxy, amino, mono- - ( C^Cg-alkyl) amino or di-(C-^Cg-alkyl) - 3 4 amino, R is Cj-Cg-alkyl or halogen, R 10 5 18 is c1-Cg-alkyl/ R is Cj-Cg.-alkoxy, 6 7 R is hydrogen or C, -c,-alkyl and R X 0 is Cj-Cg-alkyl or halogen, or a pharmaceutically acceptable salt of a carboxylic 5 acid of formula I.

3. Ethyl (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8- 10 -tetramethyl-2-naphthyl)-2,4,6-octatrienoate.

4. Ethyl 4,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l--yl)-2,4,6,8-nonatetraenoate, ethyl (all-E)-9-(4-methoxy--2,3,6-trimethylphenyl)-4,7-dimethyl-2,4,6,8-nonatetraenoate, (all-E)-4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8- 15 -tetramethyl-2-naphthyl)-2,4,6-octatrienoic acid or N- -ethyl 4-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--2-naphthyl)-2,4,6-octatrienamide.

5. A compound of formula I given in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of 20 formula X for the treatment of neoplasms, premalignant lesions, acne, psoriasis or rheumatic diseases of an inflammatory or degenerative kind.

6. A pharmaceutical preparation based on a compound of formula I given in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of formula I.

7. A process for the manufacture of a compound of formula I given in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of formula X, which process comprises reacting a compound of the general formula R^TV with a compound of the general formula II fH3 B- CH=C—CH*=CH—COR1 2 2 2 , wherein R and R have the significance given in claim 1 and either A represents a 1-(triphenylphosphonium)-ethyl group of the formula H,C-CH-P[X]_+y”, in which X represents •3 | J phenyl and Y- represents the anion of an organic or inorganic acid, and B represents formyl; or A represents acetyl and B represents dialkoxyphosphinylmethyl group of the formula -CH2-P[Z]2, in which Z represents a C^-Cg 0 -alkoxy group; and, if desired, converting a carboxylic acid ester obtained into a carboxylic acid or a carboxylic acid amide and, also if desired, converting a carboxylic acid obtained into a pharmaceutically acceptable salt. 20

8. A compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of formula I, which is any one of those specifically hereinbefore mentioned. 5

9. A process for the manufacture of a compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of formula X, substantially as hereinbefore described with particular reference to Examples 1-5 of the accompanying Examples.

10. 10. A compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable salt of a carboxylic acid of formula I, whenever prepared by a process claimed in claim 7 or 9.

11. A pharmaceutical preparation according to claim 6, 15 substantially as hereinbefore described with particular reference to Example A of the accompanying Examples. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.